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Estring

Estring(estradiol) – Pharmacia & Upjohn

BOXED WARNING

Estrogens increase the risk of endometrial cancer. Perform adequate diagnostic measures, including endometrial sampling, to rule out malignancy with undiagnosed persistent or recurrent abnormal vaginal bleeding. Should not be used for the prevention of cardiovascular disease or dementia. Increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary embolism (PE), and deep vein thrombosis (DVT) in postmenopausal women (50-79 yrs of age) reported. Increased risk of developing probable dementia in postmenopausal women ≥65 yrs of age reported. Should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risks.

THERAPEUTIC CLASS

Estrogen

INDICATIONS

Treatment of moderate to severe urogenital symptoms due to postmenopausal atrophy of the vagina and/or the lower urinary tract.

ADULT DOSAGE

Adults: Insert ring deeply into upper 1/3 of vaginal vault. Remove after 90 days and replace if appropriate. Reassess need to continue treatment at 3 or 6 month intervals.

HOW SUPPLIED

Vaginal Ring: 7.5mcg/24hrs [2mg]

CONTRAINDICATIONS

Undiagnosed abnormal genital bleeding, known/suspected/history of breast cancer, known/suspected estrogen-dependent neoplasia, active or history of DVT/PE, active or recent (within the past year) arterial thromboembolic disease (eg, stroke, MI), liver dysfunction or disease, known/suspected pregnancy.

WARNINGS/PRECAUTIONS

D/C immediately if stroke, DVT, PE, or MI occur or are suspected. Caution in patients with risk factors for arterial vascular disease and/or venous thromboembolism (VTE). If feasible, d/c at least 4 to 6 weeks before surgery associated with increased risk of thromboembolism, or during prolonged immobilization. May increase risk of breast/endometrial/ovarian cancer and gallbladder disease. Consider addition of progestin for women with a uterus or with residual endometriosis post-hysterectomy. May lead to severe hypercalcemia in patients with breast cancer and bone metastases; d/c and take appropriate measures if hypercalcemia occurs. Retinal vascular thrombosis reported; d/c pending examination if sudden partial/complete loss of vision, sudden onset of proptosis, diplopia, or migraine occurs, or if examination reveals papilledema or retinal vascular lesions. May elevate BP, thyroid binding globulin levels, and plasma TG leading to pancreatitis and other complications. Caution with history of cholestatic jaundice; d/c in case of recurrence. Caution with impaired liver function and severe hypocalcemia. May cause fluid retention; caution with cardiac/renal dysfunction. May exacerbate endometriosis, asthma, diabetes mellitus (DM), epilepsy, migraine or porphyria, systemic lupus erythematosus (SLE), and hepatic hemangiomas; use with caution. May be expelled from the vagina during bowel movement, straining or with constipation; if occurs, rinse with lukewarm water and reinsert. A narrow vagina, vaginal stenosis, prolapse, or a vaginal infection may make the vagina more susceptible to irritation or ulceration. If a vaginal infection develops, remove and reinsert only after the infection is appropriately treated. May affect certain endocrine and blood components in laboratory tests.

ADVERSE REACTIONS

Headache, leukorrhea, back pain, genital moniliasis, sinusitis, vaginitis, vaginal discomfort, vaginal hemorrhage, arthritis, insomnia, abdominal pain, upper respiratory tract infection, asymptomatic genital bacterial growth, arthralgia, flu-like symptoms.

DRUG INTERACTIONS

CYP3A4 inducers (eg, St. John's wort, phenobarbital, carbamazepine, rifampin) may decrease levels, which may decrease therapeutic effects and/or change uterine bleeding profile. CYP3A4 inhibitors (eg, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, grapefruit juice) may increase levels, which may result in side effects. Patients concomitantly receiving thyroid replacement therapy and estrogens may require increased doses of thyroid replacement therapy.

PREGNANCY

Contraindicated in pregnancy, not for use in nursing.

MECHANISM OF ACTION

Estrogen; binds to nuclear receptors in estrogen-responsive tissues. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone and follicle stimulating hormone, through a negative feedback mechanism. Reduces elevated levels of these hormones in postmenopausal women.

PHARMACOKINETICS

Absorption: Well absorbed. Estradiol: Cmax=63.2pg/mL; Tmax=0.5-1 hr. Estrone (metabolite): Cmax=66.3pg/mL. Distribution: Largely bound to sex hormone binding globulin and albumin; found in breast milk. Metabolism: Liver to estrone (metabolite) and estriol (major urinary metabolite); sulfate and glucuronide conjugation (liver); intestinal hydrolysis; CYP3A4 (partial metabolism). Elimination: Urine (parent compound and metabolites).

ASSESSMENT

Assess for undiagnosed abnormal genital bleeding, presence/history of breast cancer, estrogen-dependent neoplasia, DVT, PE, active or recent (within past yr) arterial thromboembolic disease, pregnancy, any other conditions where treatment is contraindicated or cautioned, need for progestin therapy, and for possible drug interactions. Assess use in patients ≥65 yrs and those with hypertriglyceridemia, hypothyroidism, hypocalcemia, asthma, DM, epilepsy, migraines or porphyria, or SLE.

MONITORING

Monitor for signs/symptoms of cardiovascular events, malignant neoplasms, dementia, gallbladder disease, hypercalcemia, visual abnormalities, elevations in serum triglycerides, pancreatitis, hypothyroidism, fluid retention, exacerbation of endometriosis, and other conditions. Perform annual breast exam; schedule mammography based on age, risk factors, and prior mammogram results. Regularly monitor BP, thyroid function in patients on thyroid replacement therapy, and periodically evaluate (q3 or q6 months) to determine need for continuing therapy. In cases of undiagnosed, persistent, or recurring abnormal vaginal bleeding in patients with a uterus, perform adequate diagnostic measures (eg, endometrial sampling) to rule out malignancy.

PATIENT COUNSELING

Inform that therapy increases risk for uterine cancer and may increase chances of getting a heart attack, stroke, breast cancer, and blood clots. Instruct to contact physician if breast lumps, unusual vaginal bleeding, dizziness or faintness, changes in speech, severe headaches, chest pain, SOB, leg pains, vision changes, vomiting, or yellowing of the skin, eyes, or nail beds occur. Advise to have yearly breast examinations by a physician and to perform monthly self-examinations. Instruct to notify physician if pregnant/nursing or plan to become pregnant. Inform that the ring may be expelled from the vagina during bowel movement, straining or with constipation; instruct to rinse with lukewarm water and reinsert if expelled. Advise to remove ring if a vaginal infection develops and reinsert only after the infection is appropriately treated.

ADMINISTRATION/STORAGE

Administration: Intravaginal route. Refer to PI for instruction on proper insertion, use, and removal. Storage: 15-30°C (59-86°F).


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    Estring

    Estring

    Pronunciation Generic Name: estradiol

    Dosage Form: vaginal ring

    For ProfessionalsSide EffectsInteractionsMore…

    Estring®

    (estradiol vaginal ring)

    PHYSICIAN’S LEAFLET

    Warnings

    ENDOMETRIAL CANCER

    Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)

    CARDIOVASCULAR AND OTHER RISKS

    Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)

    The Women’s Health Initiative (WHI) estrogen alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with daily oral conjugated estrogens (CE 0.625 mg) relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.)

    The estrogen plus progestin WHI substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)

    The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

    In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

    Estring Description

    Estring® (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form the ring. When placed in the vagina, Estring releases estradiol, approximately 7.5 mcg per 24 hours, in a consistent stable manner over 90 days. Estring has the following dimensions: outer diameter 55 mm; cross-sectional diameter 9 mm; core diameter 2 mm. One Estring should be inserted into the upper third of the vaginal vault, to be worn continuously for three months.

    Estradiol is chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular formula of estradiol is C18H24O2 and the structural formula is:

              

    The molecular weight of estradiol is 272.39.

    Estring – Clinical Pharmacology

    Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

    The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

    Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

    Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

    Pharmacokinetics

    A. Absorption Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

    In a Phase I study of 14 postmenopausal women, the insertion of Estring (estradiol vaginal ring) rapidly increased serum estradiol (E2) levels. The time to attain peak serum estradiol levels (Tmax) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined rapidly over the next 24 hours and were virtually indistinguishable from the baseline mean (range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E1) over the following 12 weeks during which the ring was maintained in the vaginal vault remained relatively unchanged (see Table 1).

    The initial estradiol peak post-application of the second ring in the same women resulted in ~38 percent lower Cmax, apparently due to reduced systemic absorption via the treated vaginal epithelium. The relative systemic exposure from the initial peak of Estring accounted for approximately 4 percent of the total estradiol exposure over the 12-week period.

    The release of estradiol from Estring was demonstrated in a Phase II study of 222 postmenopausal women who inserted up to four rings consecutively at three-month intervals. Systemic delivery of estradiol from Estring resulted in mean steady state serum estradiol estimates of 7.8, 7.0, 7.0, 8.1 pg/mL at weeks 12, 24, 36, and 48, respectively. Similar reproducibility is also seen in levels of estrone. The systemic exposure to estradiol and estrone was within the range observed in untreated women after the first eight hours.

    In postmenopausal women, mean dose of estradiol systemically absorbed unchanged from Estring is ~8 percent [95 percent CI: 2.8–12.8 percent] of the daily amount released locally.

    TABLE 1: PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE Estring APPLICATION
    Estrogen Cmax

    (pg/mL)

    Css–48 hr

    (pg/mL)

    Css–4w

    (pg/mL)

    Css–12w

    (pg/mL)

    *
    n=14
    Based on means
    Estradiol (E2) 63.2* 11.2 9.5 8.0
    Baseline-adjusted E2 55.6 3.6 2.0 0.4
    Estrone (E1) 66.3 52.5 43.8 47.0
    Baseline-adjusted E1 20.0 6.2 -2.4 0.8

    B. Distribution The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

    C. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

    D. Excretion Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

    Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks post-application of Estring in a Phase I study was 5 percent and 8 percent, respectively, of the daily released amount.

    E. Special Populations Estring has not been studied in patients with hepatic or renal impairment.

    F. Drug Interactions No formal drug interactions studies have been done with Estring.

    In vitro and in vivo studies have shown that systemic estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in systemic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

    Clinical Studies

    Effects on vulvar and vaginal atrophy

    Two pivotal controlled studies have demonstrated the efficacy of Estring (estradiol vaginal ring) in the treatment of postmenopausal urogenital symptoms due to estrogen deficiency.

    In a U.S. study where Estring was compared with conjugated estrogens vaginal cream, no difference in efficacy between the treatment groups was found with respect to improvement in the physician’s global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving Estring and cream, respectively) and in the patient’s global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving Estring and cream, respectively) after 12 weeks of treatment. In an Australian study, Estring was also compared with conjugated estrogens vaginal cream and no difference in the physician’s assessment of improvement of vaginal mucosal atrophy (79 percent and 75 percent for Estring and cream, respectively) or in the patient’s assessment of improvement in vaginal dryness (82 percent and 76 percent for Estring and cream, respectively) after 12 weeks of treatment.

    In the U.S. study, symptoms of dysuria and urinary urgency improved in 74 percent and 65 percent, respectively, of patients receiving Estring as assessed by the patient. In the Australian study, symptoms of dysuria and urinary urgency improved in 90 percent and 71 percent, respectively, of patients receiving Estring as assessed by the patient.

    In both studies, Estring and conjugated estrogens vaginal cream had a similar ability to reduce vaginal pH levels and to mature the vaginal mucosa (as measured cytologically using the maturation index and/or the maturation value) after 12 weeks of treatment. In supportive studies, Estring was also shown to have a similar significant treatment effect on the maturation of the urethral mucosa.

    Endometrial overstimulation, as evaluated in non-hysterectomized patients participating in the U.S. study by the progestogen challenge test and pelvic sonogram, was reported for none of the 58 (0 percent) patients receiving Estring and 4 of the 35 patients (11 percent) receiving conjugated estrogens vaginal cream.

    Of the U.S. women who completed 12 weeks of treatment, 95 percent rated product comfort for Estring as excellent or very good compared with 65 percent of patients receiving conjugated estrogens vaginal cream, 95 percent of Estring patients judged the product to be very easy or easy to use compared with 88 percent of cream patients, and 82 percent gave Estring an overall rating of excellent or very good compared with 58 percent for the cream.

    Women’s Health Initiative Studies

    The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction [MI], silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

    The estrogen alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included 10,739 women (average age 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 6.8 years are presented in Table 2.

    TABLE 2: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI
    Event Relative Risk

    CE vs. Placebo

    (95% nCI*)

    Placebo

    n = 5,429

    CE

    n = 5,310

    Absolute Risk per 10,000 Women-Years
    *
    Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
    Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
    Not included in Global index.
    §
    Results are based on an average follow-up of 6.8 years.
    All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
    #
    A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.
    CHD events† 0.95 (0.79–1.16) 56 53
      Nonfatal MI 0.91 (0.73–1.14) 43 40
      CHD death 1.01 (0.71–1.43) 16 16
    Stroke† 1.37 (1.09–1.73) 33 45
      Ischemic 1.55 (1.19–2.01) 25 38
    Deep vein thrombosis†, 1.47 (1.06–2.06) 15 23
    Pulmonary embolism† 1.37 (0.90–2.07) 10 14
    Invasive breast cancer† 0.80 (0.62–1.04) 34 28
    Colorectal cancer§ 1.08 (0.75–1.55) 16 17
    Hip fracture§ 0.61 (0.41–0.91) 17 11
    Vertebral fractures§, 0.62 (0.42–0.93) 17 11
    Total fractures§, 0.70 (0.63–0.79) 195 139
    Death due to other causes§, 1.08 (0.88–1.32) 50 53
    Overall mortality§, 1.04 (0.88–1.22) 78 81
    Global index§,# 1.01 (0.91–1.12) 190 192

    For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

    Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no overall difference from primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 2).

    Centrally adjudicated results for stroke events from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtypes or severity, including fatal strokes, in women receiving CE alone compared to placebo. Estrogen alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined (see Table 2).

    The estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years (relative risk [RR] 1.15, 95 percent nCI 1.03–1.28).

    For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

    Results of the estrogen plus progestin substudy, which included 16,608 women (average of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 3. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

    TABLE 3: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARS*
    Event Relative Risk

    CE/MPA vs. placebo

    (95% nCI†)

    Placebo

    n = 8,102

    CE/MPA

    n = 8,506

    Absolute Risk per 10,000 Women-Years
    *
    Results are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI, 0.82–1.18).
    Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
    Includes metastasis and non-metastatic breast cancer, with the exception of in situ breast cancer.
    CHD events 1.24 (1.00–1.54) 33 39
      Nonfatal MI 1.28 (1.00–1. 63) 25 31
      CHD death 1.10 (0.70–1.75) 8 8
    All strokes 1.31 (1.02–1.68) 24 31
      Ischemic Stroke 1.44 (1.09–1.90) 18 26
    Deep vein thrombosis 1.95 (1.43–2.67) 13 26
    Pulmonary embolism 2.13 (1.45–3.11) 8 18
    Invasive breast cancer‡ 1.24 (1.01–1.54) 33 41
    Invasive colorectal cancer 0.56 (0.38–0.81) 16 9
    Endometrial cancer 0.81 (0.48–1.36) 7 6
    Cervical cancer 1.44 (0.47–4.42) 1 2
    Hip fracture 0.67 (0.47–0.96) 16 11
    Vertebral fracture 0.65 (0.46–0.92) 17 11
    Lower arm/wrist fractures 0.71 (0.59–0.85) 62 44
    Total fractures 0.76 (0.69–0.83) 199 152

    Women’s Health Initiative Memory Study

    The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia (primary outcome) compared with placebo.

    After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95 percent CI, 0.83–2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)

    The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia (primary outcome) compared with placebo.

    After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI, 1.21–3.48) compared to placebo.

    When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19–2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)

    Indications and Usage for Estring

    Estring (estradiol vaginal ring) is an estrogen indicated for the treatment of moderate to severe urogenital symptoms due to postmenopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).

    Contraindications

    Estring vaginal ring should not be used in women with any of the following conditions:

    1. Undiagnosed abnormal genital bleeding.
    2. Known, suspected, or history of cancer of the breast.
    3. Known or suspected estrogen-dependent neoplasia.
    4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
    5. Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction).
    6. Known liver dysfunction or disease.
    7. Known hypersensitivity to any of the ingredients in Estring.
    8. Known or suspected pregnancy.

    Warnings

    See BOXED WARNINGS

    Estring is a vaginal administered product with low systemic absorption following continuous use for 3 months (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption). The estrogen plus progestin substudy of WHI utilized systemically-absorbed oral estrogen/progestin. However, the warnings, precautions, and adverse reactions associated with oral estrogen and/or progestin therapy should be considered in the absence of comparable data with other dosage forms of estrogens and/or progestins.

    1. Cardiovascular disorders

    An increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen alone therapy. An increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogens with or without progestins should be discontinued immediately.

    Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

    a. Stroke In the Women’s Health Initiative (WHI), estrogen alone substudy, a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens (CE 0.625 mg) compared to placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. (See CLINICAL STUDIES.)

    In the estrogen plus progestin substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES.)

    b. Coronary heart disease In the estrogen alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI and CHD death) was reported in women receiving estrogen alone compared to placebo. (See CLINICAL STUDIES.)

    In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 versus 33 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. (See CLINICAL STUDIES.)

    In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]) treatment with daily CE 0.625 mg/MPA 2.5 mg demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year one, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the combined continuous CE/MPA treatment group and the placebo group in HERS, HERS II, and overall.

    c. Venous thromboembolism (VTE) In the estrogen alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]) was reported to be increased for women receiving daily CE compared to women receiving placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years. (See CLINICAL STUDIES.)

    In the estrogen plus progestin substudy of WHI, a statistically significant two-fold greater rate of VTE was reported in women receiving daily CE/MPA compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL STUDIES.)

    If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

    2. Malignant neoplasms

    a. Endometrial cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12-times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15 to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

    Clinical surveillance of all women taking estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens result in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

    b. Breast cancer The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. Observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

    The most important randomized clinical trial providing information about this issue is the Women Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) (see CLINICAL STUDIES). In the estrogen alone substudy of WHI, after an average of 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62–1.04).

    In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nCI, 1.01–1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups.

    The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast exams by a healthcare provider and perform monthly self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

    c. Ovarian cancer The estrogen plus progestin substudy of WHI reported that daily CE/MPA increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent nCI, 0.77–3.24) but was not statistically significant. The absolute risk for CE/MPA was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

    3. Dementia

    In the estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to daily conjugated estrogens (CE 0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo.

    In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the CE alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen CE alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE alone versus placebo was 37 versus 25 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)

    In the estrogen plus progestin substudy, after an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)

    When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19–2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and PRECAUTIONS, Geriatric Use.)

    4. Gallbladder disease

    A two- to four-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

    5. Hypercalcemia

    Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

    6. Visual abnormalities

    Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued.

    Precautions

    A. General

    1. Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

    There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL), and impairment of glucose tolerance.

    2. Elevated blood pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

    3. Hypertriglyceridemia In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of treatment if pancreatitis or other complications develop.

    4. Impaired liver function and past history of cholestatic jaundice Estring vaginal ring should be used with caution in patients with impaired liver function. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

    5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

    6. Hypocalcemia Estrogens should be used with caution in individuals with severe hypocalcemia.

    7. Fluid retention Estrogens may cause some degree of fluid retention. Patients who have conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

    8. Exacerbation of endometriosis Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

    9. Exacerbation of other conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

    10. Location of Estring Some women have experienced moving or gliding of Estring within the vagina. Instances of Estring being expelled from the vagina in connection with moving the bowels, strain, or constipation have been reported. If this occurs, Estring can be rinsed in lukewarm water and reinserted into the vagina by the patient.

    11. Vaginal Irritation Estring may not be suitable for women with narrow, short, or stenosed vaginas. Narrow vagina, vaginal stenosis, prolapse, and vaginal infections are conditions that make the vagina more susceptible to Estring-caused irritation or ulceration. Women with signs or symptoms of vaginal irritation should alert their physician.

    12. Vaginal Infection Vaginal infection is generally more common in postmenopausal women due to the lack of the normal flora of fertile women, especially lactobacillus, and the subsequent higher pH. Vaginal infections should be treated with appropriate antimicrobial therapy before initiation of Estring. If a vaginal infection develops during use of Estring, then Estring should be removed and reinserted only after the infection has been appropriately treated.

    B. Information for the Patient

    Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estring.

    C. Laboratory Tests

    Serum follicle stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.

    D. Drug and Laboratory Test Interactions

    1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
    2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
    3. Other binding proteins may be elevated in serum, (i.e., corticosteroid binding globulin [CBG], sex hormone-binding globulin [SHBG]), leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
    4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
    5. Impaired glucose tolerance.

    E. Carcinogenesis, Mutagenesis, and Impairment of Fertility

    Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testes and liver.

    F. Pregnancy

    Estring should not be used during pregnancy. (See CONTRAINDICATIONS.)

    There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

    G. Nursing Mothers

    Estring should not be used during lactation. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug.

    H. Pediatric Use

    Estring is not indicated for pediatric use and no clinical data have been collected in children.

    I. Geriatric Use

    There have not been sufficient numbers of geriatric patients involved in studies utilizing Estring to determine whether those over 65 years of age differ from younger subjects in their response to Estring.

    In the estrogen alone substudy of the Women’s Health Initiative (WHI) study, 46 percent (n = 4,943) of subjects were 65 years of age and older, while 7.1 percent (n = 767) of subjects were 75 years of age and older. There was a higher relative risk (daily CE 0.625 mg versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older.

    In the estrogen alone substudy of the Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years of age, was randomized to receive daily conjugated estrogens (CE 0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women-years compared with placebo.

    Of the total number of subjects in the estrogen plus progestin substudy of WHI, 44 percent (n = 7,320) were 65 years of age and older, while 6.6 percent (n = 1,095) were 75 years of age and older. In women 75 years of age and older compared to women less than 75 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.

    In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomized to receive CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.

    Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer’s disease.

    When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19–2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

    Adverse Reactions

    See BOXED WARNINGS, WARNINGS and PRECAUTIONS

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    In the two pivotal controlled studies, discontinuation of treatment due to an adverse event was required by 5.4 percent of patients receiving Estring and 3.9 percent of patients receiving conjugated estrogens vaginal cream. The most common reasons for withdrawal from Estring treatment due to an adverse event were vaginal discomfort and gastrointestinal symptoms.

    The adverse events reported with a frequency of 3 percent or greater in the two pivotal controlled studies by patients receiving Estring or conjugated estrogens vaginal cream are listed in Table 4.

    Table 4: Adverse Events Reported by 3 Percent or More of Patients Receiving Either Estring or Conjugated Estrogens Vaginal Cream in Two Pivotal Controlled Studies
    ADVERSE EVENT Estring

    (n = 257)

    %

    Conjugated Estrogens Vaginal Cream (n = 129)

    %

    Musculoskeletal
      Back Pain 6 8
      Arthritis 4 2
      Arthralgia 3 5
      Skeletal Pain 2 4
    CNS/Peripheral Nervous System
      Headache 13 16
    Psychiatric
      Insomnia 4 0
    Gastrointestinal
      Abdominal Pain 4 2
      Nausea 3 2
    Respiratory
      Upper Respiratory Tract Infection 5 6
      Sinusitis 4 3
      Pharyngitis 1 3
    Urinary
      Urinary Tract Infection 2 7
    Female Reproductive
      Leukorrhea 7 3
      Vaginitis 5 2
      Vaginal Discomfort/Pain 5 5
      Vaginal Hemorrhage 4 5
      Asymptomatic Genital Bacterial Growth 4 6
      Breast Pain 1 7
    Resistance Mechanisms
      Genital Moniliasis 6 7
    Body as a Whole
      Flu-Like Symptoms 3 2
      Hot Flushes 2 3
      Allergy 1 4
    Miscellaneous
      Family Stress 2 3

    Other adverse events (listed alphabetically) occurring at a frequency of 1 to 3 percent in the two pivotal controlled studies by patients receiving Estring include: anxiety, bronchitis, chest pain, cystitis, dermatitis, diarrhea, dyspepsia, dysuria, flatulence, gastritis, genital eruption, urogenital pruritus, hemorrhoids, leg edema, migraine, otitis media, skin hypertrophy, syncope, toothache, tooth disorder, urinary incontinence.

    Post-Marketing Experience

    1. A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. TSS is a rare, but serious disease that may cause death. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body.
    2. A few cases of ring adherence to the vaginal wall, making ring removal difficult, have been reported. Vaginal wall ulceration or erosion should be carefully evaluated. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete in order to prevent the ring from adhering to the healing tissue.
    3. A few cases of bowel obstruction and vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated.

    The following additional adverse events were reported at least once by patients receiving Estring in the worldwide clinical program, which includes controlled and uncontrolled studies. A causal relationship with Estring has not been established.

    Body as a Whole: allergic reaction

    CNS/Peripheral Nervous System: dizziness

    Gastrointestinal: enlarged abdomen, vomiting

    Metabolic/Nutritional Disorders: weight decrease or increase

    Musculoskeletal: arthropathy (including arthrosis)

    Psychiatric: depression, decreased libido, nervousness

    Reproductive: breast engorgement, breast enlargement, intermenstrual bleeding, genital edema, vulval disorder

    Skin/Appendages: pruritus, pruritus ani

    Urinary: micturition frequency, urethral disorder

    Vascular: thrombophlebitis

    Vision: abnormal vision

    The following additional adverse reactions have been reported with estrogens:

    Genitourinary system: abnormal uterine bleeding/spotting; dysmenorrheal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer

    Breasts: tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer

    Cardiovascular: deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure

    Gastrointestinal: nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas

    Skin: chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism, rash

    Eyes: retinal vascular thrombosis; intolerance to contact lenses

    Central Nervous System: headache; migraine; dizziness; mental depression; exacerbation of chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia

    Miscellaneous: increase or decrease in weight; glucose intolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; angioedema; anaphylactoid/anaphylactic reactions; hypocalcemia (preexisting condition); exacerbation of asthma; increased triglycerides

    Overdosage

    Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. Treatment of overdose consists of discontinuation of Estring together with institution of appropriate symptomatic care.

    Estring Dosage and Administration

    One Estring (estradiol vaginal ring) is to be inserted as deeply as possible into the upper one-third of the vaginal vault. The ring is to remain in place continuously for three months, after which it is to be removed and, if appropriate, replaced by a new ring. The need to continue treatment should be assessed at 3 or 6 month intervals.

    Should the ring be removed or fall out at any time during the 90-day treatment period, the ring should be rinsed in lukewarm water and re-inserted by the patient, or, if necessary, by a physician or nurse.

    Retention of the ring for greater than 90 days does not represent overdosage but will result in progressively greater underdosage with the attendant risk of loss of efficacy and increasing risk of vaginal infections and/or erosions.

    Instructions for Use

    Estring (estradiol vaginal ring) insertion

    The ring should be pressed into an oval and inserted into the upper third of the vaginal vault. The exact position is not critical. When Estring is in place, the patient should not feel anything. If the patient feels discomfort, Estring is probably not far enough inside. Gently push Estring further into the vagina.

    Estring use

    Estring should be left in place continuously for 90 days and then, if continuation of therapy is deemed appropriate, replaced by a new Estring.

    The patient should not feel Estring when it is in place and it should not interfere with sexual intercourse. Straining at defecation may make Estring move down in the lower part of the vagina. If so, it may be pushed up again with a finger.

    If Estring is expelled totally from the vagina, it should be rinsed in lukewarm water and reinserted by the patient (or doctor/nurse if necessary).

    Estring removal

    Estring may be removed by hooking a finger through the ring and pulling it out.

    For patient instructions, see Patient Information.

    How is Estring Supplied

    Each Estring (estradiol vaginal ring) is individually packaged in a heat-sealed rectangular pouch consisting of three layers, from outside to inside: polyester, aluminum foil, and low density polyethylene, respectively. The pouch is provided with a tear-off notch on one side.

    NDC 0013-2150-36 Estring (estradiol vaginal ring) 2 mg – available in single packs.

    STORAGE

    Store at controlled room temperature 15° to 30° C (59° to 86° F).

    Rx only

    LAB-0082-5.0

    August 2008

    PATIENT INFORMATION

    Estring

    (estradiol vaginal ring)

    Read this PATIENT INFORMATION before you start using Estring and read the patient information each time you refill your Estring prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms and their treatment.

    What is the most important information I should know about Estring (an estrogen hormone)?

    • Estrogens increase the chance of getting cancer of the uterus.

    Report any unusual vaginal bleeding right away while you are using Estring. Vaginal bleeding after menopause may be a warning sign of cancer of the uterine (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

    • Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes, or dementia.

    Using estrogens with or without progestins may increase your chance of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with or without progestins may increase your risk of dementia, based on a study of women age 65 years or older.

    You and your healthcare provider should talk regularly about whether you still need treatment with Estring.

    What is Estring?

    Estring (estradiol vaginal ring) is an off-white, soft, flexible ring with a center that contains 2 mg of estradiol (an estrogen hormone). Estring releases estradiol into the vagina in a consistent, stable manner for 90 days. The soft, flexible ring is placed in the upper third of the vagina (by the physician or the patient). Estring should be removed after 90 days of continuous use. If continuation of therapy is indicated, the flexible ring should be replaced.

    What is Estring used for?

    Estring is used after menopause to:

    • Treat moderate to severe itching, burning, and dryness in or around the vagina.

    You and your healthcare provider should talk regularly about whether you still need treatment with Estring to control these problems.

    Who should not use Estring?

    Do not start using Estring if you:

    • Have unusual vaginal bleeding
    • Currently have or have had certain cancers Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should use Estring.
    • Had a stroke or heart attack in the past year
    • Currently have or have had blood clots
    • Currently have or have had liver problems
    • Are allergic to any of the ingredients in Estring See the list of ingredients in Estring at the end of this leaflet.
    • Think you may be pregnant

    Tell your healthcare provider:

    • If you are breastfeeding The hormone in Estring can pass into your breast milk.

    • About all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
    • About all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Estring works. Estring may also affect how your other medicines work.
    • If you are going to have surgery or will be on bed rest You may need to stop taking estrogens.

    How should I use Estring?

    Estring is a local estrogen therapy designed to relieve itching, burning and dryness in and around the vagina . Estring PROVIDES RELIEF OF LOCAL SYMPTOMS OF MENOPAUSE ONLY.

    Estrogens should be used only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with Estring.

    Estring INSERTION

    Estring can be inserted and removed by you or your doctor or healthcare provider. To insert Estring yourself, choose the position that is most comfortable for you: standing with one leg up, squatting, or lying down.

    1. After washing and drying your hands, remove Estring from its pouch using the tear-off notch on the side. (Since the ring becomes slippery when wet, be sure your hands are dry before handling it.)
    2. Hold Estring between your thumb and index finger and press the opposite sides of the ring together as shown.
    3. Gently push the compressed ring into your vagina as far as you can.

    Estring PLACEMENT

    The exact position of Estring is not critical, as long as it is placed in the upper third of the vagina.

    When Estring is in place, you should not feel anything. If you feel uncomfortable, Estring is probably not far enough inside. Use your finger to gently push Estring further into your vagina.

    There is no danger of Estring being pushed too far up in the vagina or getting lost. Estring can only be inserted as far as the end of the vagina, where the cervix (the narrow, lower end of the uterus) will block Estring from going any further (see diagram of Female Anatomy).

    Estring USE

    Once inserted, Estring should remain in place in the vagina for 90 days.

    Most women and their partners experience no discomfort with Estring in place during intercourse, so it is NOT necessary that the ring be removed. If Estring should cause you or your partner any discomfort, you may remove it prior to intercourse (see Estring Removal, below). Be sure to reinsert Estring as soon as possible afterwards.

    Estring may slide down into the lower part of the vagina as a result of the abdominal pressure or straining that sometimes accompanies constipation. If this should happen, gently guide Estring back into place with your finger.

    There have been rare reports of Estring falling out in some women following intense straining or coughing. If this should occur, simply wash Estring with lukewarm (NOT hot) water and reinsert it.

    Estring DRUG DELIVERY

    Once in the vagina, Estring begins to release estradiol immediately. Estring will continue to release a low, continuous dose of estradiol for the full 90 days it remains in place.

    It will take about 2 to 3 weeks to restore the tissue of the vagina and urinary tract to a healthier condition and to feel the full effect of Estring in relieving vaginal and urinary symptoms. If your symptoms persist for more than a few weeks after beginning Estring therapy, contact your doctor or healthcare provider.

    One of the most frequently reported effects associated with the use of Estring is an increase in vaginal secretions. These secretions are like those that occur normally prior to menopause and indicate that Estring is working. However, if the secretions are associated with a bad odor or vaginal itching or discomfort, be sure to contact your doctor or healthcare provider.

    Estring REMOVAL

    After 90 days there will no longer be enough estradiol in the ring to maintain its full effect in relieving your vaginal or urinary symptoms. Estring should be removed at that time and replaced with a new Estring, if your doctor determines that you need to continue your therapy.

    To remove Estring:

    1. Wash and dry your hands thoroughly.
    2. Assume a comfortable position, either standing with one leg up, squatting, or lying down.
    3. Loop your finger through the ring and gently pull it out.
    4. Discard the used ring in a waste receptacle. (Do not flush Estring.)

    If you have any additional questions about removing Estring, contact your doctor or healthcare provider.

    What are the possible side effects of Estring?

    A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. Toxic shock syndrome is a rare but serious illness caused by a bacterial infection. If you have fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-like rash on face and body, remove Estring and contact your healthcare provider. A few cases of the vaginal ring becoming attached to the vaginal wall, making ring removal difficult, have been reported.

    The most frequently reported side effect with Estring use is increased vaginal secretions. Many of these vaginal secretions are like those that occur normally prior to menopause and indicate that Estring is working. Vaginal secretions that are associated with a bad odor, vaginal itching, or other signs of vaginal infection are NOT normal and may indicate a risk or a cause for concern. Other side effects may include vaginal discomfort, abdominal pain, or genital itching.

    What are the possible side effects of estrogens ?

    Side effects are grouped by how serious they are and how often they happen when you are treated.

    Serious but less common side effects include:

    • Breast cancer
    • Cancer of the uterus
    • Stroke
    • Heart attack
    • Blood clots
    • Dementia
    • Gallbladder disease
    • Ovarian cancer
    • High blood pressure
    • Liver problems
    • High blood sugar
    • Enlargement of benign tumors of the uterus (“fibroids”)  

        Some of the warning signs of these serious side effects include:

      • Breast lumps
      • Unusual vaginal bleeding
      • Dizziness and faintness
      • Changes in speech
      • Severe headaches
      • Chest pain
      • Shortness of breath
      • Pains in your legs
      • Changes in vision
      • Vomiting
      • Yellowing of the skin, eyes or nail beds  

        Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

    Less serious but common side effects include:

    • Headache
    • Breast pain
    • Irregular vaginal bleeding or spotting
    • Stomach/abdominal cramps, bloating
    • Nausea and vomiting
    • Hair loss
    • Fluid retention
    • Vaginal yeast infection

    These are not all the possible side effects of estrogens. For more information, ask your healthcare provider or pharmacist.

    What can I do to lower my chances of getting a serious side effect with Estring?

    • Follow carefully the instructions for use.
    • Talk with your healthcare provider regularly about whether you should continue using Estring.
    • See your healthcare provider right away if you get vaginal bleeding while using Estring.
    • If you have fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-like rash on face and body, remove Estring and contact your healthcare provider.
    • Contact your healthcare provider if you have difficulty removing the vaginal ring.
    • Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast examinations more often.
    • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.

    General information about safe and effective use of Estring

    Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Estring for conditions for which it was not prescribed. Do not give Estring to other people, even if they have the same symptoms you have. It may harm them.

    Keep Estring out of the reach of children.

    This leaflet provides a summary of the most important information about Estring. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Estring that is written for health professionals. You can get more information by calling the toll free number 1-888-691-6813.

    What are the ingredients in Estring?

    Estring (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol (an estrogen hormone). Estradiol, silicone polymers and barium sulfate are combined to form the ring.

    Storage: Store at controlled room temperature 15° to 30° C (59° to 86° F).

    LAB-0087-4.0

    August 2008

    PRINCIPAL DISPLAY PANEL – 2 mg Ring Carton

    NDC 63539-021-01

    PROFESSIONAL SAMPLE – NOT FOR SALE

    Rx only

    Estring®

    estradiol vaginal ring

    2 mg

    1 unit

    Estring 

    estradiol ring

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:63539-021
    Route of Administration VAGINAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    estradiol (estradiol) estradiol 2 mg
    Inactive Ingredients
    Ingredient Name Strength
    barium sulfate  
    Packaging
    # Item Code Package Description
    1 NDC:63539-021-01 1 RING (RING) in 1 POUCH
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA020472 04/26/1996
    Labeler - U.S. Pharmaceuticals (829076905)

    Revised: 01/2012   U.S. Pharmaceuticals

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    Estring

    Estring

    Pronunciation Generic Name: estradiol (Vaginal route)

    es-tra-DYE-ol

    OverviewSide EffectsInteractionsFor ProfessionalsMore… Vaginal route(Cream) Estrogens increase the risk of endometrial cancer; monitor for abnormal vaginal bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) have been reported. An increased risk of developing probable dementia in postmenopausal women 65 years of age or older has also been reported. Risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins. Estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration possible .

    Vaginal route(Insert, Extended Release) Estrogens increase the risk of endometrial cancer; monitor for abnormal vaginal bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. Increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) using estrogen alone have been reported. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) using estrogens combined with progestins have been reported. An increased risk of developing probable dementia in postmenopausal women 65 years of age or older has also been reported in women receiving estrogen alone or estrogen combined with progestins. Risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins. Estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration possible .

    Vaginal route(Tablet) There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens and adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. The Women’s Health Initiative (WHI) reported increased risks of stroke and DVT with the use of estrogen-alone therapy and increased risks of stroke, DVT, pulmonary embolism, myocardial infarction, and invasive breast cancer with the use of estrogen plus progestin. In addition, the WHI memory study reported an increased risk of probable dementia in postmenopausal women 65 years of age and older who used estrogen alone or in combination with progestin therapy. Estrogen therapy with or without progestins should not be used for the prevention of cardiovascular disease or dementia, and should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman .

    Vaginal route(Insert, Extended Release) Estrogens increase the risk of endometrial cancer; monitor for abnormal vaginal bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) have been reported. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman .

    Commonly used brand name(s)

    In the U.S.

    • Estrace
    • Estring
    • Femring
    • Vagifem

    Available Dosage Forms:

    • Tablet
    • Cream
    • Insert, Extended Release

    Therapeutic Class: Endocrine-Metabolic Agent

    Pharmacologic Class: Estrogen

    Uses For Estring

    Estradiol vaginal is a medicine that contains an estrogen hormone. It is used to treat changes in and around the vagina (such as vaginal dryness, itching, and burning) caused by low estrogen levels or menopause.

    This medicine is available only with your doctor’s prescription.

    Before Using Estring

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Use of Vagifem® vaginal tablet is not indicated for children.

    Geriatric

    Although appropriate studies on the relationship of age to the effects of Vagifem® vaginal tablets have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have breast cancer, strokes, or dementia, which may require caution in patients receiving this medicine.

    Pregnancy

    Pregnancy Category Explanation
    All Trimesters X Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

    Breast Feeding

    Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Isotretinoin
    • Theophylline
    • Tizanidine
    • Tranexamic Acid

    Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Alprazolam
    • Amprenavir
    • Aprepitant
    • Atazanavir
    • Bacampicillin
    • Betamethasone
    • Bexarotene
    • Bosentan
    • Carbamazepine
    • Clarithromycin
    • Colesevelam
    • Cyclosporine
    • Darunavir
    • Delavirdine
    • Efavirenz
    • Etravirine
    • Fosamprenavir
    • Fosaprepitant
    • Fosphenytoin
    • Ginseng
    • Griseofulvin
    • Itraconazole
    • Ketoconazole
    • Lamotrigine
    • Levothyroxine
    • Licorice
    • Modafinil
    • Mycophenolate Mofetil
    • Mycophenolic Acid
    • Nelfinavir
    • Nevirapine
    • Oxcarbazepine
    • Phenobarbital
    • Phenytoin
    • Pioglitazone
    • Prednisolone
    • Primidone
    • Rifabutin
    • Rifampin
    • Rifapentine
    • Ritonavir
    • Rosuvastatin
    • Rufinamide
    • Selegiline
    • St John’s Wort
    • Tacrine
    • Telaprevir
    • Tipranavir
    • Topiramate
    • Troglitazone
    • Troleandomycin
    • Voriconazole
    • Warfarin

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

    • Caffeine
    • Grapefruit Juice

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Abnormal or unusual vaginal bleeding or
    • Blood clots (e.g., deep vein thrombosis, pulmonary embolism), active or history of or
    • Breast cancer, known or suspected, or a history of or
    • Heart attack, history of or
    • Liver disease or
    • Protein C, protein S, or other known blood clotting disorders or
    • Stroke, history of or
    • Tumors (estrogen-dependent), known or suspected—Should not be used in patients with these conditions.
    • Angioedema or anaphylaxis—Should not be used in patients who have experienced these conditions with prior Vagifem® use.
    • Asthma or
    • Diabetes or
    • Edema (fluid retention or body swelling) or
    • Endometriosis or
    • Epilepsy (seizures) or
    • Gallbladder disease or
    • Hereditary angioedema (swelling of the face, lips, tongue, or throat) or
    • Hypercalcemia (high calcium in the blood) or
    • Hypocalcemia (low calcium in the blood) or
    • Hypothyroidism (an underactive thyroid) or
    • Hypertriglyceridemia or
    • Jaundice during pregnancy or from using hormonal therapy in the past or
    • Liver tumors or
    • Migraine headache or
    • Porphyria (an enzyme problem) or
    • Systemic lupus erythematosus (SLE)—Use with caution. May make these conditions worse.
    • Heart disease or
    • Hypertension (high blood pressure) or
    • Hypercholesterolemia (high cholesterol or fats in the blood) or
    • Obesity, or history of or
    • Prolonged periods of immobilization—Use with caution. These conditions may increase risk for more serious side effects.

    Proper Use of estradiol

    This section provides information on the proper use of a number of products that contain estradiol. It may not be specific to Estring. Please read with care.

    It is very important that you use this medicine exactly as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects.

    This medicine comes with a patient information leaflet. Read and follow the instructions in the leaflet carefully. Ask your doctor if you have any questions.

    To use the vaginal tablet:

    • The tablet should be used only in your vagina. Do not swallow the tablet.
    • Each vaginal tablet comes packaged inside an applicator. Do not take the tablet out of the applicator. If the tablet comes out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. If the tablet falls out of the applicator, throw it away and use a new applicator that still has the tablet inside it.
    • Keep your hands clean and dry while handling the tablet.
    • Take the applicator out of the plastic wrap before using it.
    • Use the applicator only one time and then throw it away. Use a new applicator for each dose.
    • Most women will start by inserting a new tablet every day for two weeks, then change to inserting a new tablet only 2 days each week. Carefully follow the schedule that your health caregiver tells you to.

    Dosing

    The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    • For vaginal dosage form (tablet):
      • For treatment of atrophic vaginitis caused by menopause:
        • Adults—10 microgram (mcg) or one tablet inserted into the vagina once a day for 2 weeks, followed by one tablet twice weekly.
        • Children—Use is not recommended.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    Storage

    Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

    Keep out of the reach of children.

    Do not keep outdated medicine or medicine no longer needed.

    Ask your healthcare professional how you should dispose of any medicine you do not use.

    Precautions While Using Estring

    It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and does not cause unwanted effects. Pelvic exam, breast exam, and mammogram (breast x-ray) may be needed to check for unwanted effects, unless your doctor tells you otherwise. Be sure to keep all appointments.

    It is unlikely that a postmenopausal woman may become pregnant. But, you should know that using this medicine while you are pregnant could harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

    Using this medication may increase your risk of endometrial cancer, breast cancer, or uterine cancer. Talk with your doctor about this risk. If you still have your uterus (womb), ask your doctor if you should also use a progestin medicine. Check with your doctor immediately if your experience abnormal vaginal bleeding.

    Using this medicine may increase your risk of dementia, especially in women 65 years of age and older.

    Using this medicine may increase your risk for having blood clots, strokes, or heart attacks. This risk may continue even after you stop using the medicine. Your risk for these serious problems is even greater if you have high blood pressure, high cholesterol in your blood, diabetes or are overweight or smoke cigarettes. Contact your doctor immediately if you experience chest pain, confusion, difficulty speaking, double vision, headaches, an inability to move arms, legs or facial muscle, or an inability to speak.

    Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine before you have surgery or if you need to stay in bed for an extended time. This medicine may affect the results of certain medical tests.

    Check with your doctor immediately if severe headache or sudden loss of vision or any other change in vision occurs while you are using this medicine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

    Do not eat grapefruit or drink grapefruit juice while you are using this medicine. Grapefruit and grapefruit juice may change the amount of this medicine that is absorbed in the body.

    Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John’s wort) or vitamin supplements.

    Estring Side Effects

    Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor immediately if any of the following side effects occur:

    Less common

    • Vaginal yeast infection

    Incidence not known

    • Change in vaginal discharge
    • clear or bloody discharge from the nipple
    • decrease in the amount of urine
    • dimpling of the breast skin
    • fast heartbeat
    • fever
    • hives
    • hoarseness
    • inverted nipple
    • irritation
    • itching
    • joint pain, stiffness, or swelling
    • lump in the breast or under the arm
    • noisy, rattling breathing
    • pain or feeling of pressure in the pelvis
    • pain, redness, or swelling in the arm or leg
    • persistent crusting or scaling of the nipple
    • rash
    • redness of the skin
    • redness or swelling of the breast
    • shortness of breath
    • sore on the skin of the breast that does not heal
    • swelling of the eyelids, face, fingers, lips, hands, feet, or lower legs
    • tightness in the chest
    • troubled breathing at rest
    • troubled breathing or swallowing
    • vaginal bleeding

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    More common

    • Abdominal or stomach pain
    • back pain
    • headache
    • itching or pain of the vagina or genital area
    • thick, white vaginal discharge with mild or no odor
    • weight gain

    Less common

    • Body aches or pain
    • chills
    • cough
    • diarrhea
    • ear congestion
    • loss of voice
    • nasal congestion
    • runny nose
    • sneezing
    • sore throat
    • unusual tiredness or weakness

    Incidence not known

    • Feeling sad or empty
    • headache, severe and throbbing
    • hives or welts
    • irritability
    • itching
    • lack of appetite
    • tiredness
    • trouble concentrating
    • trouble sleeping

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    See also: Estring Vaginal side effects (in more detail)

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    Estring

    Estring

    Generic Name: estrogen (Vaginal route)

    Commonly used brand name(s)

    In the U.S.

    • Estrace
    • Estring
    • Femring
    • Ortho Dienestrol
    • Premarin
    • Vagifem

    In Canada

    • Estragyn
    • Neo-Estrone
    • Oestrilin

    Available Dosage Forms:

    • Tablet
    • Cream
    • Insert, Extended Release
    • Suppository

    Uses For Estring

    Estrogens are hormones produced by the body. Among other things, estrogens help develop and maintain female organs.

    When your body is in short supply of this hormone, replacing it can ease the uncomfortable changes that occur in the vagina, vulva (female genitals), and urethra (part of the urinary system). Conditions that are treated with vaginal estrogens include a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), and inflammation of the urethra (atrophic urethritis).

    Estrogens work partly by increasing a normal clear discharge from the vagina and making the vulva and urethra healthy. Using or applying an estrogen relieves or lessens:

    • Dryness and soreness in the vagina
    • Itching, redness, or soreness of the vulva
    • Feeling an urge to urinate more often then is needed or experiencing pain while urinating
    • Pain during sexual intercourse

    When used vaginally or on the skin, most estrogens are absorbed into the bloodstream and cause some, but not all, of the same effects as when they are taken by mouth. Estrogens used vaginally at very low doses for treating local problems of the genitals and urinary system will not protect against osteoporosis or stop the hot flushes caused by menopause.

    Estrogens for vaginal use are available only with your doctor’s prescription.

    Before Using Estring

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Estrogen vaginal cream is not indicated in children. Studies have not been conducted.

    Geriatric

    Elderly women greater than 65 years of age may have an increased risk of certain side effects during treatment, especially stroke, invasive breast cancer, and memory problems.

    Pregnancy

    Estrogens should not be used during pregnancy, since an estrogen called diethylstilbestrol (DES) that is no longer taken for hormone replacement has caused serious birth defects in humans and animals.

    Breast Feeding

    Use of this medicine is not recommended in nursing mothers. Estrogens pass into the breast milk and may decrease the amount and quality of breast milk. Caution should be exercised in mothers who are using estrogen and breast-feeding.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

    Other Medical Problems

    The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

    • Asthma or
    • Epilepsy or
    • Heart problems or
    • Kidney problems or
    • Migraine headaches—Estrogens may worsen these conditions.
    • Blood clotting problems—Although worsening of a blood clotting condition is unlikely, some doctors do not prescribe vaginal estrogens for patients with blood clotting problems or a history of these problems.
    • Breast cancer (active, suspected, or past history)—Estrogens should not be used.
    • Certain cancers, including cancers of the breast, bone, or uterus (active or suspected)—Estrogens may interfere with the treatment of breast or bone cancer or worsen cancer of the uterus when these conditions are present.
    • Cholestatic jaundice (flow of bile from the liver is blocked), past history—Caution should be used when this condition is present.
    • Diabetes mellitus (sugar diabetes)—Estrogens may alter your body’s response to sugar in your diet.
    • Endometriosis or
    • Fibroid tumors of the uterus—Estrogens may worsen endometriosis or increase the size of fibroid tumors.
    • Gallbladder problems (gallstones)—Estrogens may increase your chance of getting a gallbladder attack.
    • Heart attack or
    • Stroke (active or past history)—Estrogens should not be used.
    • Hepatic hemangioma (noncancerous tumors of the liver)—Estrogens may worsen this medical problem.
    • High blood pressure—Estrogens may worsen this medical problem.
    • Hypercalcemia (too much calcium in your blood)—Estrogens may worsen this medical problem.
    • Hypertriglyceridemia (too much triglycerides in your blood)—Estrogens may increase your chance of getting pancreatitis or other side effects.
    • Hypocalcemia (too little calcium in your blood)—Your doctor should treat the low calcium in your blood before starting estrogen therapy.
    • Irritation or infection of the vagina—Usually estrogens decrease infections or irritation of the vagina, but sometimes these conditions may become worse.
    • Liver disease or
    • Liver problems—Estrogens should not be used.
    • Lupus erythematosus, systemic (SLE or lupus)—Estrogens may worsen this medical problem.
    • Physical problems within the vagina, such as narrow vagina, vaginal stenosis, or vaginal prolapse—Estradiol vaginal insert or ring may be more likely to slip out of place or cause problems, such as irritation of the vagina.
    • Porphyria—Estrogens may worsen this medical problem.
    • Thyroid problems (underactive thyroid)—Estrogens may alter your body’s response to your thyroid medication. Your doctor may alter the amount of thyroid replacement that you take while on estrogen therapy.
    • Vision changes, sudden onset including
    • Bulging eyes or
    • Double vision or
    • Migraine headache or
    • Vision loss, partial or complete—Estrogens may cause these problems. Tell your doctor if you have had any of these problems.
    • Unusual genital or vaginal bleeding of unknown causes—Use of estrogens may delay diagnosis or worsen the condition. The reason for the bleeding should be determined before estrogens are used.

    Proper Use of estrogen

    This section provides information on the proper use of a number of products that contain estrogen. It may not be specific to Estring. Please read with care.

    Vaginal estrogen products usually come with patient directions. Read them carefully before using this medicine.

    Wash your hands before and after using the medicine. Also, keep the medicine out of your eyes. If this medicine does get into your eyes, wash them out immediately, but carefully, with large amounts of tap water. If your eyes still burn or are painful, check with your doctor.

    Use this medicine only as directed. Do not use more of it and do not use it for a longer time than your doctor ordered. It can take up to 4 months to see the full effect of the estrogens. Your doctor may reconsider continuing your estrogen treatment or may lower your dose several times within the first one or two months, and every 3 to 6 months after that. Sometimes a switch to oral estrogens may be required for added benefits or for higher doses. When using the estradiol vaginal insert or ring, you will need to replace it every 3 months or remove it after 3 months.

    For vaginal creams or suppositories:

    • Vaginal creams and some vaginal suppositories are inserted with a plastic applicator. Directions for using the applicator are supplied with your medicine. If you do not see your dose marked on the applicator, ask your health care professional for more information.
    • To fill the applicator for cream dosage forms:
      • Screw the applicator onto the tube.
      • Squeeze the medicine into the applicator slowly until it is measured properly.
      • Remove the applicator from the tube. Replace the cap on the tube.
    • To fill the applicator for suppository dosage form:
      • Place the suppository into the applicator.
    • To place the dose using the applicator for cream and suppository dosage forms:
      • Relax while lying on your back with your knees bent or stand with one foot on a chair.
      • Hold the full applicator in one hand. Slide the applicator slowly into the vagina. Stop before it becomes uncomfortable.
      • Slowly press the plunger until it stops.
      • Withdraw the applicator. The medicine will be left behind in the vagina.
    • To care for the applicator for cream and suppository dosage forms:
      • Clean the applicator after use by pulling the plunger out of the applicator and washing both parts completely in warm, soapy water. Do not use hot or boiling water.
      • Rinse well.
      • After drying the applicator, replace the plunger.

    For vaginal insert or ring dosage form:

    • To place the vaginal insert:
      • Relax while lying on your back with your knees bent or stand with one foot on a chair.
      • Pinch or press the sides of the vaginal insert together, between your forefinger and middle finger.
      • With one hand, part the folds of skin around your vagina.
      • Slide the vaginal insert slowly into the upper third of your vagina. Stop before it becomes uncomfortable. The exact location is not too important but it should be comfortable.
      • If it seems uncomfortable, then carefully push the vaginal insert higher into the vagina.
    • To remove the vaginal insert:
      • Stand with one foot on a chair.
      • Slide one finger into the vagina and hook it around the closest part of the vaginal insert.
      • Slowly pull the vaginal insert out.
      • Dispose of the vaginal insert by wrapping it up and throwing it into the trash. Do not flush it down the toilet.

    Dosing

    The dose medicines in this class will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    • For conjugated estrogens
    • For vaginal dosage form (cream):
      • For treating inflammation of the vagina (atrophic vaginitis):
        • Adults—At first, 0.5 gram (g) of conjugated estrogens inserted into the vagina once a day or as directed by your doctor to achieve the lowest dose possible. Usually your doctor will want you to use this medicine for only three weeks of each month (three weeks on and one week off). Your doctor may increase your dose as needed. However, the dose is usually not more than 2 grams per day.
      • For treating a genital skin condition (vulvar atrophy):
      • Adults—0.5 gram (g) of conjugated estrogens inserted into the vagina two times per week. Usually your doctor will want you to use this medicine for only three weeks of each month (three weeks on and one week off).
    • For estradiol
    • For vaginal dosage form (cream):
      • For treating a genital skin condition (vulvar atrophy) and inflammation of the vagina (atrophic vaginitis):
        • Adults—200 to 400 micrograms (mcg) of estradiol (two to four grams of cream) inserted into the vagina once a day for one to two weeks, decreasing the dose by one half over two and four weeks. After four weeks, your doctor will probably ask you to use the medicine less often, such as 100 mcg (one gram of cream) one to three times a week and for only three weeks of each month (three weeks on and one week off).
    • For vaginal dosage form (insert or ring):
      • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis) in postmenopausal women, and inflammation of the urethra (urethritis) in postmenopausal women:
        • Adults—One insert containing 2 to 24.8 milligrams (mg) of estradiol inserted into the vagina every three months. The insert will slowly release estradiol at a rate of 7.5 to 100 micrograms (mcg) every twenty-four hours with continuous use.
    • For estrone
    • For vaginal dosage form (cream):
      • For treating a genital skin condition (vulvar atrophy) and inflammation of the vagina (atrophic vaginitis) in postmenopausal women:
        • Adults—2 to 4 milligrams (mg) of estrone (two to four grams of cream) inserted into the vagina once a day or as directed by your doctor.
    • For vaginal dosage form (suppository):
      • For treating a genital skin condition (vulvar atrophy) and inflammation of the vagina (atrophic vaginitis) in postmenopausal women:
        • Adults—250 to 500 micrograms (mcg) inserted into the vagina once a day or as directed by your doctor.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    When using the suppository or cream several times a week: If you miss a dose of this medicine and remember it within 1 or 2 days of the missed dose, use the missed dose as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    When using the cream or suppositories more than several times a week: If you miss a dose of this medicine, use it as soon as possible if remembered within 12 hours of the missed dose. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    Storage

    Keep out of the reach of children.

    Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

    Do not keep outdated medicine or medicine no longer needed.

    Precautions While Using Estring

    It is very important that your doctor check your progress at regular visits to make sure this medicine does not cause unwanted effects. Plan on going to see your doctor every year, but some doctors require visits more often.

    It is not yet known whether the use of vaginal estrogens increases the risk of breast cancer in women. It is very important that you check your breasts on a regular basis for any unusual lumps or discharge. Report any problems to your doctor. You should also have a mammogram (x-ray picture of the breasts) done if your doctor recommends it.

    It is important that you have a regular pelvic exam (pap smear). Your doctor will tell you how often this exam should be done.

    Talk to your doctor if you have high blood pressure, high cholesterol (fats in the blood), or diabetes, use tobacco, or are overweight. You may have a higher risk for getting heart disease.

    Although the chance is low, use of estrogen may increase your chance of getting cancer of the ovary or uterus (womb). Regular visits to your health professional can help identify these serious side effects early.

    If you think that you may be pregnant, stop using the medicine immediately and check with your doctor.

    Tell the doctor in charge that you are using this medicine before having any laboratory test, because some test results may be affected.

    For vaginal creams or suppositories:

    • Avoid using latex condoms, diaphragms, or cervical caps for up to 72 hours after using estrogen vaginal creams. Certain estrogen products may contain oils in the creams that can weaken latex (rubber) products and cause condoms to break or leak, or cervical caps or diaphragms to wear out sooner. Check with your health care professional to make sure the vaginal estrogen product you are using can be used with latex devices.
    • This medicine is often used at bedtime to increase effectiveness through better absorption.
    • Vaginal creams or suppositories will melt and leak out of the vagina. A minipad or sanitary napkin will protect your clothing. Do not use tampons (like those used for menstrual periods) since they may soak up the medicine and make the medicine less effective.
    • Avoid exposing your male sexual partner to your vaginal estrogen cream or suppository by not having sexual intercourse right after using these medicines. Your male partner might absorb the medicine through his penis if it comes in contact with the medicine.

    For estradiol vaginal inserts or rings:

    • Contact your doctor if you have problems removing your vaginal insert.
    • It is not necessary to remove the vaginal insert for sexual intercourse unless you prefer to remove it.
    • If you do take it out, or if it accidentally slips or comes out of the vagina, you can replace the vaginal insert in the vagina after washing it with lukewarm water. Never use hot or boiling water.
    • If it slips down, gently push it upwards and back into place.
    • Replace the vaginal insert every 3 months.
    • Talk to your doctor on a regular basis about how long to use the vaginal insert.

    Estring Side Effects

    The risk of any serious adverse effect is unlikely for most women using low doses of estrogens vaginally. Even women with special risks have used vaginal estrogens without problems.

    Check with your doctor immediately if any of the following side effects occur:

    Less common

    • Breast pain
    • enlarged breasts
    • itching of the vagina or genitals
    • headache
    • nausea
    • stinging or redness of the genital area
    • thick, white vaginal discharge without odor or with a mild odor

    Rare

    • Feeling of vaginal pressure (with estradiol vaginal insert or ring)
    • unusual or unexpected uterine bleeding or spotting
    • vaginal burning or pain (with estradiol vaginal insert or ring)

    Incidence not known

    • Diarrhea
    • dizziness
    • fast heartbeat
    • feeling faint
    • fever
    • hives
    • hoarseness
    • itching
    • joint pain, stiffness, or swelling
    • muscle pain
    • rash
    • shortness of breath
    • skin redness
    • swelling of eyelids, face, lips, hands, or feet
    • tightness in the chest
    • trouble with breathing or swallowing
    • vomiting
    • wheezing

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    Less common

    • Abdominal or back pain
    • clear vaginal discharge (usually means the medicine is working)

    Incidence not known

    • Acne
    • enlargement of penis or testes
    • growth of pubic hair
    • rapid increase in height
    • swelling of the breasts or breast soreness in males

    Also, many women who are using estrogens with a progestin (another female hormone) will start having monthly vaginal bleeding that is similar to menstrual periods. This effect will continue for as long as the medicine is taken. However, monthly bleeding will not occur in women who have had the uterus removed by surgery (hysterectomy).

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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    Estring

    Estring

    Generic Name: estradiol (topical) (ess tra DYE ole)

    Brand Name: Estrace Vaginal Cream, Estring

    OverviewSide EffectsInteractionsMore…

    What is estradiol?

    Estradiol (a form of estrogen) is a female sex hormone necessary for many processes in the body. Estradiol vaginal products release estrogen that is absorbed directly through the skin of the vaginal wall.

    Estradiol topical is used to treat certain symptoms of menopause such as dryness, burning, and itching of the vaginal area and urgency or irritation with urination.

    Estradiol may also be used for purposes other than those listed in this medication guide.

    What is the most important information I should know about estradiol?

    Estradiol increases the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus. Taking progestins, another hormone drug, while using estradiol lowers the risk of developing this condition. Therefore, if your uterus has not been removed, your doctor may prescribe a progestin for you to take together while using estradiol. Visit your doctor regularly and report any unusual vaginal bleeding right away.

    Treatment with estradiol long-term may increase the risk of stroke. Because of this risk, you should contact your doctor or healthcare provider to discuss your individual risks and benefits before taking estradiol long-term. You should also talk to your doctor or healthcare provider on a regular basis (for example, every 3-6 months) about whether you should continue this treatment.

    Have yearly physical exams and examine your breasts for lumps on a monthly basis while using estradiol.

    Do not use this medication if you are pregnant.

    The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50-79 years of age) during 5 years of treatment with oral conjugated estrogens combined with medroxyprogesterone acetate.

    The Women’s Health Initiative Memory Study (WHIMS) found that postmenopausal women 65 years of age or older who were treated with oral conjugated estrogens plus medroxyprogesterone acetate had an increased risk of developing dementia. It is unknown whether this finding applies to younger postmenopausal women or to women using estrogen only therapy.

    What should I discuss with my healthcare provider before using estradiol?

    Do not use estradiol without first talking to your doctor if you have

    • a circulation, bleeding, or blood-clotting disorder;

    • undiagnosed, abnormal vaginal bleeding; or
    • any type of breast, uterine, or hormone-dependent cancer.

    Using estradiol may be dangerous in some cases if you have any of the conditions listed above.

    Before using estradiol, tell your doctor if you have

    • high blood pressure, angina, or heart disease;

    • high levels of cholesterol or triglycerides in your blood;
    • liver disease;
    • kidney disease;
    • asthma;
    • epilepsy;
    • migraines;
    • diabetes;
    • depression;
    • gallbladder disease;
    • uterine fibroids;
    • had a hysterectomy (uterus removed);
    • a narrow, short, or prolapsed vagina;
    • vaginal irritation; or
    • a vaginal infection.

    You may not be able to use estradiol, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

    Treatment with estradiol long-term may increase the risk of stroke. Because of this risk, you should contact your doctor or healthcare provider to discuss your individual risks and benefits before taking estradiol long-term. You should also talk to your doctor or healthcare provider on a regular basis (for example, every 3-6 months) about whether you should continue this treatment.

    The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50-79 years of age) during 5 years of treatment with oral conjugated estrogens combined with medroxyprogesterone acetate.

    The Women’s Health Initiative Memory Study (WHIMS) found that postmenopausal women 65 years of age or older who were treated with oral conjugated estrogens plus medroxyprogesterone acetate had an increased risk of developing dementia. It is unknown whether this finding applies to younger postmenopausal women or to women using estrogen only therapy.

    Estradiol is in the FDA pregnancy category X. This means that estradiol will cause birth defects in an unborn baby. Do not use estradiol if you are pregnant or are planning a pregnancy.

    Estradiol may decrease milk flow and have other effects on milk composition. Do not use estradiol without first talking to your doctor if you are breast-feeding a baby.

    How should I use estradiol?

    Use estradiol exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

    To use the Estring vaginal ring:

    • Squeeze the sides of the ring together and insert it into the vagina as far as possible (into the upper 1/3 of the vagina). You should not be able to feel the ring once it is in position. If you can feel it, use a finger to push it further into the vagina. It is not possible for the ring to go too far in or become lost.

    • The ring should remain in place for 90 days. It should then be removed and replaced by a new ring, if prescribed by your doctor. If at any time the ring falls out, rinse it with warm water and reinsert it. If it slides down into the lower part of the vagina, use a finger to reinsert it.
    • The ring does not need to be removed during sexual intercourse. It should not be felt by either partner. If it is bothersome, it can be removed, rinsed with warm water, and reinserted following intercourse.
    • To remove the ring, loop a finger through the ring and gently pull it from the vagina.

    To use the estradiol vaginal cream:

    • Using the marked applicator provided, measure the prescribed dose of cream.

    • Lie on your back with your knees drawn up, sit, or stand in a position that allows you comfortable access to the vaginal area. To deliver the medication, gently insert the applicator deeply into your vagina and press the plunger downward to its original position.
    • Clean the applicator by pulling the plunger to remove it from the barrel. Wash it with mild soap and warm water.

    Have yearly physical exams and examine your breasts for lumps on a monthly basis while using estradiol.

    Store the vaginal rings and cream at room temperature away from moisture and heat.

    What happens if I miss a dose?

    Insert the next dose of cream or ring as soon as you remember. Continue to follow your regular schedule. Do not use two doses simultaneously unless your doctor directs otherwise.

    If at any time the ring falls out, rinse it with warm water and reinsert it. If it slides down into the lower part of the vagina, use a finger to reinsert it.

    What happens if I overdose?

    An overdose of estradiol is unlikely to occur and is not likely to threaten life. If you do suspect an overdose, or if the medication has been ingested, call an emergency room or poison control center for advice.

    What should I avoid while using estradiol?

    There are no restrictions on food, beverages, or activity while using estradiol unless your doctor directs otherwise.

    Estradiol side effects

    Estradiol increases the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus. Taking progestins, another hormone drug, while using estradiol lowers the risk of developing this condition. Therefore, if your uterus has not been removed, your doctor may prescribe a progestin for you to take together while using estradiol. Visit your doctor regularly and report any unusual vaginal bleeding right away.

    Treatment with estradiol long-term may increase the risk of stroke. Because of this risk, you should contact your doctor or healthcare provider to discuss your individual risks and benefits before taking estradiol long-term. You should also talk to your doctor or healthcare provider on a regular basis (for example, every 3-6 months) about whether you should continue this treatment.

    If you experience any of the following serious side effects, stop using estradiol and seek emergency medical attention:

    • an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);

    • shortness or breath or pain in the chest;
    • a painful, red, swollen leg;
    • abnormal vaginal bleeding;
    • pain, swelling, or tenderness in the abdomen;
    • severe headache or vomiting, dizziness, faintness or changes in vision or speech;
    • yellowing of the skin or eyes; or
    • a lump in a breast.

    Other, less serious side effects may be more likely to occur. Continue to use estradiol and talk to your doctor if you experience

    • decreased appetite, nausea, or vomiting;

    • swollen breasts;
    • acne or skin color changes;
    • decreased sex drive;
    • migraine headaches or dizziness;
    • vaginal pain, dryness, or discomfort;
    • water retention (swollen hands, feet, or ankles);
    • depression; or
    • changes in your menstrual cycle or break-through bleeding.

    Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

    See also: Estring side effects (in more detail)

    What other drugs will affect estradiol?

    Before using estradiol, tell your doctor if you are taking any of the following medicines:

    • an anticoagulant (blood thinner) such as warfarin (Coumadin);

    • a thyroid medication such as levothyroxine (Synthroid, Levoxyl, Levothroid, and others);
    • insulin or an oral diabetes medicine such as glipizide (Glucotrol), glyburide (Diabeta, Micronase), and others; or
    • tamoxifen (Nolvadex).

    A dosage adjustment or special monitoring may be required during treatment if you are taking any of the medicines listed above.

    Do not use other vaginal products at the same times as estradiol without first talking to your doctor.

    Drugs other than those listed here may also interact with estradiol. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

    Next Page → Side Effects

    More Estring resources

    • Side Effects
    • Pregnancy Warnings
    • Drug Interactions
    • Support Group
    • 8 Reviews - Add your own review/rating

    Compare Estring with other medications

    • Atrophic Urethritis
    • Atrophic Vaginitis
    • Hypoestrogenism

    Where can I get more information?

    • Your pharmacist has additional information about estradiol written for health professionals that you may read.

    What does my medication look like?

    Estradiol is available with a prescription under the brand name Estrace as a vaginal cream and under the brand name Estring as a vaginal ring. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

    • Estrace Vaginal Cream-42.5 g tube with a plastic applicator

    • Estring Vaginal Ring-2 mg

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    Estring

    Estring

    Generic Name: estradiol vaginal (local) (ES tra DYE ole VA jin ul (LO kul))

    Brand Name: Estrace Vaginal, Estring, Vagifem

    OverviewSide EffectsInteractionsMore…

    What is estradiol vaginal (local)?

    Estradiol is a form of estrogen, a female sex hormone that regulates many processes in the body.

    Some estradiol products placed directly into the vagina are used for “local” treatment of vaginal menopause symptoms involving the secretions and surrounding tissues of the vagina. Other vaginal estradiol products are used for treating menopause symptoms affecting the vagina as well as other parts of the body (such as hot flashes). This type of vaginal estradiol has “systemic” effects, meaning that it can affect parts of the body other than where the medicine is placed or applied.

    The information in this leaflet is specific to estradiol vaginal products that are used for local treatment of symptoms. Estradiol vaginal (local) is used to treat vaginal symptoms of menopause such as dryness, burning, and itching. Estradiol vaginal also reduces urgency or irritation of urination.

    Estradiol should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

    Estradiol vaginal (local) may also be used for purposes not listed in this medication guide.

    What is the most important information I should know about estradiol vaginal (local)?

    Estradiol can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

    You should not use this medication if you have any of the following conditions: liver disease, a bleeding disorder, unusual vaginal bleeding, a history of breast or uterine cancer, or if you have ever had a heart attack, stroke, or a blood clot.

    Long-term use of estradiol may increase your risk of breast cancer, uterine cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risks before using estradiol vaginal long term.

    Report any unusual vaginal bleeding right away. Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using estradiol vaginal.

    Estradiol vaginal should not be used to prevent heart disease, stroke, or dementia, because this medicine may actually increase your risk of developing these conditions.

    What should I discuss with my healthcare provider before using estradiol vaginal (local)?

    You should not use this medication if you are allergic to estradiol, if you are pregnant, or if you have:

    • liver disease;

    • a bleeding or blood-clotting disorder;
    • a history of heart attack, stroke, or blood clot;
    • unusual vaginal bleeding that a doctor has not checked; or
    • any type of breast, uterine, or hormone-dependent cancer.

    To make sure you can safely use estradiol vaginal, tell your doctor if you have any of these other conditions:

    • heart disease;

    • risk factors for coronary artery disease (such as diabetes, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease);
    • hereditary angioedema (an immune system disorder);
    • a history of jaundice caused by pregnancy or birth control pills;
    • a thyroid disorder;
    • kidney disease;
    • asthma;
    • epilepsy or other seizure disorder;
    • migraines;
    • endometriosis or uterine fibroid tumors;
    • lupus;
    • gallbladder disease; or
    • high levels of calcium in your blood.

    Estradiol may increase your risk of developing a condition that may lead to uterine cancer. Your doctor may prescribe a progestin to take while you are using estradiol, to help lower this risk. Report any unusual vaginal bleeding right away.

    Long-term use of estradiol may increase your risk of breast cancer, heart attack, stroke, or blood clot. Talk with your doctor about your individual risks before using estradiol vaginal long term.

    FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use estradiol if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medication.

    Estradiol can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.

    How should I use estradiol vaginal (local)?

    Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

    This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

    Wash your hands before and after inserting estradiol vaginal.

    You should not be able to feel the vaginal ring once it is in place. Leave the vaginal ring in place for 90 days, then remove it. Your doctor may want you to replace it with a new ring.

    Use the applicator provided to measure the prescribed dose of estradiol vaginal cream. Take apart the cream applicator and wash it with mild soap and warm water after each use.

    Each estradiol vaginal tablet is supplied in a single-use disposable applicator. Throw the tablet applicator away after one use.

    Your doctor should check your progress on a regular basis (every 3 to 6 months). Self-examine your breasts for lumps on a monthly basis while using estradiol vaginal.

    If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medication for a short time. Any doctor or surgeon who treats you should know that you are using estradiol.

    Store at room temperature away from moisture and heat. Keep the vaginal ring in its protective pouch until you are ready to use it.

    What happens if I miss a dose?

    Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose. Remove the vaginal ring and insert a new one as soon as you remember. Do not use an extra vaginal ring to make up the missed wearing time.

    What happens if I overdose?

    Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include nausea, vomiting, and vaginal bleeding.

    What should I avoid while using estradiol vaginal (local)?

    Avoid using other vaginal products without your doctor’s advice.

    Grapefruit and grapefruit juice may interact with estradiol and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

    Estradiol vaginal (local) side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

    Remove the vaginal ring and seek emergency medical attention if you have: fever with nausea, vomiting, diarrhea, muscle pain, dizziness, fainting, and/or sunburn-like skin rash. These may be signs of a life-threatening disease called toxic shock syndrome.

    Stop using this medication and call your doctor at once if you have a serious side effect such as:

    • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

    • sudden numbness or weakness, sudden severe headache, sudden vision changes, problems with speech or balance;
    • sudden cough, wheezing, rapid breathing, coughing up blood;
    • pain, swelling, warmth, or redness in one or both legs;
    • swelling or tenderness in your stomach;
    • jaundice (yellowing of the skin or eyes);
    • unusual vaginal bleeding;
    • a lump in your breast;
    • numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes; or
    • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

    Less serious side effects may include:

    • breast swelling and tenderness, nipple discharge;

    • vaginal itching or discharge;
    • mild nausea, stomach cramps, diarrhea, bloating;
    • swelling of your ankles or feet;
    • migraine headaches or dizziness;
    • cold symptoms such as stuffy nose, sneezing, sore throat;
    • acne or skin color changes, increased facial hair, thinning scalp hair;
    • depressed mood; or
    • changes in your menstrual periods, break-through bleeding.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Estring side effects (in more detail)

    What other drugs will affect estradiol vaginal (local)?

    Tell your doctor about all other medicines you use, especially:

    • St. John’s wort;

    • an antibiotic or antifungal medication (Biaxin, Ery-Tab, Erythrocin, Ketek, Mycobutin, Nizoral, Noxafil, Rifater, Sporanox, Vfend, Zithromax, Zmax, and others);
    • a barbiturate such as phenobarbital (Solfoton);
    • heart or blood pressure medication such as nicardipine (Cardene) or quinidine (Quin-G);
    • the hepatitis C medications boceprevir (Victrelis) or telaprevir (Incivek);
    • HIV/AIDS medication such as efavirenz (Sustiva, Atripla), fosamprenavir (Lexiva), indinavir (Crixivan), ritonavir (Norvir, Kaletra), and others;
    • seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), phenytoin (Dilantin), and others; or
    • thyroid replacement therapy (levothyroxine, Synthroid, Levothroid, Levoxyl, and others).

    This list is not complete and there are many other drugs that can interact with estradiol. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

    Next Page → Side Effects

    More Estring resources

    • Side Effects
    • Pregnancy Warnings
    • Drug Interactions
    • Support Group
    • 8 Reviews - Add your own review/rating

    Compare Estring with other medications

    • Atrophic Urethritis
    • Atrophic Vaginitis
    • Hypoestrogenism

    Where can I get more information?

    • Your pharmacist can provide more information about estradiol vaginal.

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